Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids

• Published in: Cell metabolism Vol. 33; no. 8; pp. 1592 - 1609.e7
• Main Authors: Hu, Wenxiang, Jiang, Chunjie, Kim, Mindy, Yang, Wenjian, Zhu, Kun, Guan, Dongyin, Lv, Wenjian, Xiao, Yang, Wilson, Jessica R., Rader, Daniel J., Pui, Ching-Hon, Relling, Mary V., Lazar, Mitchell A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.08.2021
• Subjects: adipocyte; Adipocytes - metabolism; Anti-Inflammatory Agents; Dexamethasone - adverse effects; Epigenomics; gene regulation; genetic variation; glucocorticoid receptor; Glucocorticoids - adverse effects; hepatocyte; Humans; precision medicine; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; genetic variation; precision medicine; glucocorticoid receptor; hepatocyte; gene regulation; adipocyte
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2021.06.004

Glucocorticoids (GCs) are widely used as anti-inflammatory drugs, but their long-term use has severe metabolic side effects. Here, by treating multiple individual adipose stem cell-derived adipocytes and induced pluripotent stem cell-derived hepatocytes with the potent GC dexamethasone (Dex), we uncovered cell-type-specific and individual-specific GC-dependent transcriptomes and glucocorticoid receptor (GR) cistromes. Individual-specific GR binding could be traced to single-nucleotide polymorphisms (SNPs) that altered the binding motifs of GR or its cooperating factors. We also discovered another set of genetic variants that modulated Dex response through affecting chromatin accessibility or chromatin architecture. Several SNPs that altered Dex-regulated GR binding and gene expression controlled Dex-driven metabolic perturbations. Remarkably, these genetic variations were highly associated with increases in serum glucose, lipids, and body mass in subjects on GC therapy. Knowledge of the genetic variants that predispose individuals to metabolic side effects allows for a precision medicine approach to the use of clinically relevant GCs. [Display omitted] •Human adipocyte and hepatocyte responses to GCs were tested•Individual-specific genomic binding by GR determined these responses•Genetic variations control GR function and GC response•Genetic variations predict individual adverse metabolic effects of GC therapy Applying functional genomics to individual stem cell-derived adipocytes and hepatocytes, Hu et al. reveal natural genetic variations that modulate and determine the metabolic side effects of a clinically relevant glucocorticoid.